Steven Leach, M.D.
The Paul K. Neumann Professor in Pancreatic Cancer
Professor of Surgery, Oncology and Cell Biology
Contact Information
Broadway Research Bldg, Room 471
410-502-6985 (Lab)
410-955-5765 (Office)
410-614-2913 (Fax)
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Research Interests
Our laboratory studies genetic and epigenetic regulation of epithelial differentiation in exocrine pancreas, using both mouse and zebrafish model systems. By better understanding factors regulating exocrine differentiation in developing pancreas, we have been able to improve our understanding of abnormal differentiation events occurring during pancreatic tumorigenesis.
Our work has demonstrated that epithelial stem cells in adult and embryonic pancreas are regulated by specific interactions between Notch signaling and the EGF pathway. Notch is a highly conserved signaling system known to regulate cell fate decisions in a wide variety of adult and embryonic tissues. We have shown that, during normal pancreatic development, Notch reserves a population of undifferentiated precursor cells by inhibiting the activity of Ptf1a, a basic HLH protein required for formation of exocrine pancreas. Reflecting this influence, pancreatic differentiation is accelerated in zebrafish embryos with targeted defects in Notch signaling. The importance of this effect is reflected by evidence of Notch pathway activation not only in invasive pancreatic cancer, but also in pancreatic cancer precursor lesions in both mouse and human. By specifically implicating Notch signaling in the generation of pancreatic cancer precursors, we have identified an important new target for early detection and chemoprevention strategies.
Current studies in the lab are directed towards the following goals:
- Identification and characterization of epithelial progenitor cells in adult and embryonic pancreas
- Identifying novel targets of the pancreas-specific Ptf1 transcriptional complex, using genome-wide screening techniques
- Identification and characterization of novel transcription factors regulating exocrine pancreas development through mutagenesis of the zebrafish genome, using both traditional chemical mutagenesis as well as a novel transposon-mediated gene trapping approach
- Determining the role of microRNA’s in the regulation of pancreatic epithelial differentiation
- Functional annotation of the pancreatic cancer genome in zebrafish
Selected Publications
- Miyamoto Y, et al. Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3:565-576, 2003.
- Esni F, et al. Origin of exocrine pancreatic cells from nestin-positive precursors in developing mouse pancreas. Mechanisms of Development, 121:15-25, 2004.
- Lin JW, et al. Differential requirement for ptf1a in endocrine and exocrine lineages of developing zebrafish pancreas. Developmental Biology 270: 474-486, 2004.
- Esni R, et al. Notch inhibits PTF1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development, 131: 4213-4224, 2004.
- Means A, et al. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development, 132: 3767-3776, 2005.
- Ghosh B, Leach SD. Interactions between Hairy/Enhancer of Split-related proteins and the pancreatic transcription factor Ptf1-p48 modulate function of the PTF1 transcriptional complex. Biochem. J., 393:679-685, 2006.
- Davison JM, Akitake CM, Goll MG, Rhee JM, Gosse N, Baier H, Halpern ME*, Leach SD*, Parsons MJ*. Transactivation from Gal4-VP16 transgenic insertions for tissue-specific cell labeling and ablation in zebrafish. Dev Biol. 304:811-824, 2007.
- Provost E, Rhee J, Leach SD. Viral 2A peptides allow expression of multiple proteins from a single ORF in transgenic zebrafish embryos. Genesis, in press (DOI 10.10002/dvg.20338), 2007.
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